Catherine J. Mummery

A voxel-based morphometry study of semantic dementia : Relationship between temporal lobe atrophy and semantic memory

The cortical anatomy of 6 patients with semantic dementia (the temporal lobe variant of frontotemporal dementia) was contrasted with that of a group of age‐matched normal subjects by using voxel‐based morphometry, a technique that identifies changes in gray matter volume on a voxel‐by‐voxel basis. Among the circumscribed regions of neuronal loss, the left temporal pole (Brodmann area 38) was the most significantly and consistently affected region. Cortical atrophy in the left hemisphere also involved the inferolateral temporal lobe (Brodmann area 20/21) and fusiform gyrus. In addition, the right temporal pole (Brodmann area 38), the ventromedial frontal cortex (Brodmann area 11/32) bilaterally, and the amygdaloid complex were affected, but no significant atrophy was measured in the hippocampus, entorhinal, or caudal perirhinal cortex. The degree of semantic memory impairment across the 6 cases correlated significantly with the extent of atrophy of the left anterior temporal lobe but not with atrophy in the adjacent ventromedial frontal cortex. These results confirm that the anterior temporal lobe is critically involved in semantic processing, and dissociate its function from that of the adjacent frontal region. Ann Neurol 2000; 47:36–45

Functional Neuroanatomy of the Semantic System: Divisible by What?

Studies of patients with brain damage suggest that specific brain regions may be differentially involved in representing/processing certain categories of conceptual knowledge. With regard to the dissociation that has received the most attentionbetween the domains of living things and artifactsa debate continues as to whether these category-specific effects reflect neural implementation of categories directly or some more basic properties of brain organization. The present positron emission tomography (PET) study addressed this issue by probing explicitly for differential activation associated with written names of objects from the domains of living things or artifacts during similarity judgments about different attributes of these objects. Subjects viewed triads of written object names and selected one of two response words as more similar to a target word according to a specified perceptual attribute (typical color of the objects) or an associative attribute (typical location of the objects). The control task required a similarity judgment about the number of syllables in the target and response words. All tasks were performed under two different stimulus conditions: names of living things and names of artifacts. Judgments for both domains and both attribute types activated an extensive, distributed, left-hemisphere semantic system, but showed some differential activation-particularly as a function of attribute type. The left temporooccipito-parietal junction showed enhanced activity for judgments about object location, whereas the left anteromedial temporal cortex and caudate nucleus were differentially activated by color judgments. Smaller differences were seen for living and nonliving domains, the positive findings being largely consistent with previous studies using objects; in particular, words denoting artifacts produced enhanced activation in the left posterior middle temporal gyrus. These results suggest that, within a distributed conceptual system activated by words, the more prominent neural distinction relates to type of attribute.

Generating 'Tiger' as an Animal Name or a Word Beginning with T: Differences in Brain Activation

Positron emission tomography was used to investigate differences in regional cerebral activity during word retrieval in response to different prompts. The contrast of semantic category fluency and initial letter fluency resulted in selective activation of left temporal regions; the reverse contrast yielded activation in left frontal regions (BA44/6). A further comparison between types of category fluency demonstrated a more anterior temporal response for natural kinds and more posterior activation for manipulable manmade objects. These results support behavioural data suggesting that category fluency is relatively more dependent on temporal-lobe regions, and initial letter fluency on frontal structures; and that categorical word retrieval is not a uniformly distributed function within the brain. This is compatible with the category-specific deficits observed after some focal lesions.

Delineating Necessary and Sufficient Neural Systems with Functional Imaging Studies of Neuropsychological Patients

This paper demonstrates how functional imaging studies of neuropsychological patients can provide a way of determining which areas in a cognitive network are jointly necessary and sufficient. The approach is illustrated with an investigation of the neural system underlying semantic similarity judgments. Functional neuroimaging demonstrates that normal subjects activate left temporal, parietal, and inferior frontal cortices during this task relative to physical size judgments. Neuropsychology demonstrates that damage to the temporal and parietal regions results in semantic deficits, indicating that these areas are necessary for task performance. In contrast, damage to the inferior frontal cortex does not impair task performance, indicating that the inferior frontal cortex might not be necessary. However, there are two other possible accounts of intact performance following frontal lobe damage: (1) there is functional reorganization involving the right frontal cortex and (2) there is peri-infarct activity around the damaged left-hemisphere tissue. Functional imaging of the patient is required to discount these possibilities. We investigated a patient (SW), who was able to associate words and pictures on the basis of semantic relationships despite extensive damage to the left frontal, inferior parietal, and superior temporal cortices. Although SW showed peri-infarct activation in left extrasylvian temporal cortices, no activity was observed in either left or right inferior frontal cortices. These ndings demonstrate that activity in extrasylvian temporo-parietal and medial superior frontal regions is sufcient to perform semantic similarity judgments. In contrast, the left inferior frontal activations detected in each control subject appear not to be necessary for task performance. In conclusion, necessary and sufcient brain systems can be delineated by functional imaging of brain-damaged patients who are not functionally impaired.

Anatomic constraints on cognitive theories of category specificity.

Many cognitive theories of semantic organization stem from reports of patients with selective, category-specific deficits for particular classes of objects (e.g., fruit). The anatomical assumptions underlying the competing claims can be evaluated with functional neuroimaging but the findings to date have been inconsistent and insignificant when standard statistical criteria are adopted. We hypothesized that category differences in functional brain responses might be small and task dependent. To test this hypothesis, we entered data from seven PET studies into a single multifactorial design which crossed category (living vs man-made) with a range of tasks. Reliable category-specific effects were observed but only for word retrieval and semantic decision tasks. Living things activated medial aspects of the anterior temporal poles bilaterally while tools activated a left posterior middle temporal region. These category-by-task interactions provide robust evidence for an anatomical double dissociation according to category and place strong constraints on cognitive theories of the semantic system. Furthermore they reconcile some of the apparent inconsistencies between lesion studies and functional neuroimaging data.

Progressive logopenic/phonological aphasia: Erosion of the language network

The primary progressive aphasias (PPA) are paradigmatic disorders of language network breakdown associated with focal degeneration of the left cerebral hemisphere. Here we addressed brain correlates of PPA in a detailed neuroanatomical analysis of the third canonical syndrome of PPA, logopenic/phonological aphasia (LPA), in relation to the more widely studied clinico-anatomical syndromes of semantic dementia (SD) and progressive nonfluent aphasia (PNFA). 32 PPA patients (9 SD, 14 PNFA, 9 LPA) and 18 cognitively normal controls had volumetric brain MRI with regional volumetry, cortical thickness, grey and white matter voxel-based morphometry analyses. Five of nine patients with LPA had cerebrospinal fluid biomarkers consistent with Alzheimer (AD) pathology (AD-PPA) and 2/9 patients had progranulin (GRN) mutations (GRN-PPA). The LPA group had tissue loss in a widespread left hemisphere network. Compared with PNFA and SD, the LPA group had more extensive involvement of grey matter in posterior temporal and parietal cortices and long association white matter tracts. Overlapping but distinct networks were involved in the AD-PPA and GRN-PPA subgroups, with more anterior temporal lobe involvement in GRN-PPA. The importance of these findings is threefold: firstly, the clinico-anatomical entity of LPA has a profile of brain damage that is complementary to the network-based disorders of SD and PNFA; secondly, the core phonological processing deficit in LPA is likely to arise from temporo-parietal junction damage but disease spread occurs through the dorsal language network (and in GRN-PPA, also the ventral language network); and finally, GRN mutations provide a specific molecular substrate for language network dysfunction.

Noun imageability and the temporal lobes

We used positron emission tomography to investigate brain activity in response to hearing or reading nouns of varying imageability. Three experiments were performed. Activity increased with noun imageability in the left mid-fusiform gyrus, the lateral parahippocampal area in humans, and in the rostral medial temporal lobes close to or within perirhinal cortex. The left mid-fusiform activation has been observed in previous imaging studies of single word processing. Its functional significance was variously attributed to semantic processing, visual imagery, encoding episodic memories, or the integration of lexical inputs from different sensory modalities. These hypotheses are not mutually exclusive. The more rostral medial lobe response to noun imageability has not been observed previously. However, lesions in perirhinal cortex impair knowledge about objects in non-human primates, and bilateral rostral ventromedial temporal lobe potentials in response to object nouns were observed with human intracranial recordings. Imageable (object) nouns are learnt with reference to sensory experiences of living and non-living objects, whereas acquisition of the meaning of low imageable (abstract) nouns is more dependent on their context within sentences. Parahippocampal and perirhinal cortices are reciprocally connected with, respectively, second and third order sensory association cortices. We conclude that access to the representations of word meaning is dependent on heteromodal temporal lobe cortex, and that during the acquisition of object nouns one route is established through ventromedial temporal cortical regions that have reciprocal connections with all sensory association cortices.

Detecting residual cognitive function in persistent vegetative state

Despite converging agreement about the definition of persistent vegetative state, recent reports have raised concerns about the accuracy of diagnosis in some patients, and the extent to which, in a selection of cases, residual cognitive functions may remain undetected. Objective assessment of residual cognitive function can be extremely difficult as motor responses may be minimal, inconsistent, and difficult to document in many patients, or may be undetectable in others because no cognitive output is possible. Here we describe strategies for using H 2 15 O positron emission tomography activation studies to study covert cognitive processing in patients with a clinical diagnosis of persistent vegetative state. Three cases are described in detail. Of these, two exhibited clear and predicted regional cerebral blood flow responses during well-documented activation paradigms (face recognition and speech perception) which have been shown to produce specific, robust and reproducible activation patterns in normal volunteers. Some months after scanning, both patients made a significant recovery. In a third case, blood flow data were acquired during a speech perception task, although methodological difficulties precluded any systematic interpretation of the results. In spite of the multiple logistic and procedural problems involved, these results have major clinical and scientific implications and provide a strong basis for the systematic study of possible residual cognitive function in patients diagnosed as being in a persistent vegetative state.

Altered Sense of Humor in Dementia

Sense of humor is potentially relevant to social functioning in dementias, but has been little studied in these diseases. We designed a semi-structured informant questionnaire to assess humor behavior and preferences in patients with behavioral variant frontotemporal dementia (bvFTD; n = 15), semantic dementia (SD; n = 7), progressive nonfluent aphasia (PNFA; n = 10), and Alzheimer’s disease (AD; n = 16) versus healthy age-matched individuals (n = 21). Altered (including frankly inappropriate) humor responses were significantly more frequent in bvFTD and SD (all patients) than PNFA or AD (around 40% of patients). All patient groups liked satirical and absurdist comedy significantly less than did healthy controls. This pattern was reported premorbidly for satirical comedy in bvFTD, PNFA, and AD. Liking for slapstick comedy did not differ between groups. Altered sense of humor is particularly salient in bvFTD and SD, but also frequent in AD and PNFA. Humor may be a sensitive probe of social cognitive impairment in dementia, with diagnostic, biomarker and social implications.

A novel presenilin 1 deletion (p.L166del) associated with early onset familial Alzheimer's disease.

We report the case of a 40 year‐old woman who, at 38 years of age, developed insidious memory loss and, subsequently, progressive dementia satisfying criteria for probable Alzheimers disease (AD) (NINCDS‐ADRDA) [Neurology 1984; 34: 939]. Analysis of the presenilin 1 gene (PSEN1) revealed a 496_498delCTT mutation at codon 166. The amnestic presentation and absence of other features contrasts with the majority of other documented deletions which have been associated with spastic paraparesis. They are, however, consistent with the reported clinical phenotype in the majority of PSEN1 exon 6 mutations so far reported.